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Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation

Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of... Background: To explore the value of alpha fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of HBV-related hepatocellular carcinoma (HCC) and their relationship with vascular invasion, tumor differentiation and size. Methods: A total of 433 participants were enrolled in this study including 266 cases with HBV-related HCC, 87 cases with HBV DNA positive benign liver disease and 80 healthy individuals. Then we explored the correlation between AFP, PIVKA-II serum level and several pathological features such as vascular invasion, tumor differentiation and size. The value of these two markers used singly or jointly in diagnosing HBV-related HCC was evaluated by receiver operating characteristic (ROC) curve. The ROC curve was also plotted to identify AFP, PIVKA-II serum cut-off values that would best distinguish HBV-related HCC patients with and without vascular invasion. Results: The level of AFP and PIVKA-II in HBV-related HCC group was significantly higher (Z was 7.428, 11.243 respectively, all P < 0.01). When AFP and PIVKA-II were used as the individual tumor marker, the areas under the ROC curve (AUC) of HBV-related HCC diagnosis were 0.765 (95% CI, 0.713 ~ 0.8170) for AFP, 0.901 (95% CI, 0.868 ~ 0.935) for PIVKA-II, and 0.917 (95% CI, 0.886 ~ 0.948) for AFP and PIVKA-II simultaneously. The serum levels of AFP and PIVKA-II were positively correlated with tumor differentiation and size. High AFP and PIVKA-II expression was significantly associated with the presence of vascular invasion (P was 0.007 and 0.014 respectively). The AFP level > 64.4 ng/ml or PIVKA-II level > 957.61mAU/ml was the best critical value to predict the presence of vascular invasion. Conclusion: Our results validate that AFP and PIVKA-II play a significant role in the diagnosis of HBV-related HCC. The diagnostic value of AFP and PIVKA-II combined detection or single assay of PIVKA-II is higher than that of separate assay of AFP. Moreover, their concentration has important clinical value in judging tumor size, tumor cell differentiation and vascular invasion. Keywords: HBV-related hepatocellular carcinoma, Alpha-fetoprotein, PIVKA-II, Vascular invasion * Correspondence: luzhiming@sdu.edu.cn Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, PR China Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, PR China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Si et al. Infectious Agents and Cancer (2020) 15:70 Page 2 of 7 Background with healthy individuals. Participants with Haemocoagu- HCC is currently the fifth most common malignant latory disorders, vitamin K uptake disorders and intake tumor and the third leading cause of cancer related of vitamin K blocking agents were excluded. Informed death worldwide [1]. There are close relationships consents were obtained from all participants. among chronic viral hepatitis (such as Hepatitis B and Hepatitis C), posthepatitic cirrhosis and HCC [2–4]. For Measurement of AFP and PIVKA-II the lack of typical symptoms of HCC in early stage, it is The contents of AFP and PIVKA-II were detected in the generally not easy to diagnose. More than 80% HCC pa- same serum samples respectively. AFP was measured tients are diagnosed at the middle or late stages. There- using the method of immunofluorescence on automatic fore, it is urgent to identify effective and specific electrophoresis fluorescence immunoassay analyzer biomarkers that provide early predictive potential for (mTAS Wako i30, Japan). The cut-off value was set at diagnosis of HCC [5]. 20 ng/ml. Serum levels of PIVKA-II were detected by AFP is a kind of glycoprotein that is often associated chemiluminescence enzyme immunoassay on automatic with HCC. However, AFP levels also increase in preg- chemiluminescence immunoassay instrument (LUMI- nancy and some benign diseases such as severe hepatitis PULSE® G1200, Japan). The cut-off value was 40mAU/ and cirrhosis. AFP is not significantly increased in about ml. The above reagents required were all original kit and 35% ~ 40% of the HCC patients, especially for small the standard operation procedure was followed strictly HCC [6, 7]. during the test. PIVKA-II is an abnormal form of prothrombin, which has been used as a good diagnostic biomarker for HCC Confirmation of vascular invasion [8–10]. There is now considerable evidence that PIVKA- Firstly, microscopic infiltration of the vessels at the per- II is an independent prognostic factor after liver surgery, iphery of the HBV-related HCC nodules was searched in such as hepatic resection or liver transplantation [11]. In all native livers by hematoxylin-eosin (H&E) staining. addition, PIVKA-II is influenced by many non-tumor Then, tumor vessel invasion was assessed by identifying factors, such as coagulation dysfunction, liver cirrhosis neoplastic emboli within the tumor vessels stained by and so on [8]. the mouse monoclonal antibody against CD34 protein. There were few studies on the correlation between the The stained slides were blindly and randomly examined above two indicators and vascular invasion, tumor differ- by the same pathologist who had already evaluated H&E entiation and size. And the conclusions are controversial sections. [12–14]. The aim of the study was to evaluate the diag- nostic value of PIVKA-II and AFP in the diagnosis of Statistical analysis HBV-related HCC and futher analysis the level of AFP IBM SPSS statistical software (version 22.0, USA) and and PIVKA-II in HBV-related HCC patients with differ- MedCalc (version 15.2.2.0, Belgium) were used for all statis- ent clinicopathologic characteristics such as tumor dif- tical analysis. It was found that the concentration levels of ferentiation and vascular invasion. AFP and PIVKA-II were skew distribution. Each variable was represented as median with interquartile range (IQR). Materials and methods Multi-numerical variables were compared by Kruskal- Patients Wallis test, and the nonparametric Mann-Whitney test was Two hundred sixty-six cases of HBV-related hepatocel- applied to compare the differences between two numerical lular carcinoma which were newly diagnosed in variables. Log transformation was used for AFP and Shangdong Provincial Hospital from January 2017 to PIVKA-II values to analyse the large range of values among December 2018 were recruited as experimental group. the different groups for the markers. The transformed data All cases were confirmed by pathological examination. were compared by box plots. Categorical variables were Pathological report of HBV-related HCC included tumor expressed in percentage and compared with the Pearson diameter and differentiation. Vascular invasion was de- Chi-square test. ROC Curves and AUROC were calculated fined by the presence of tumor cells forming a thrombus to evaluate the diagnostic value of AFP and PIVKA-II singly in a vascular space lined by endothelial cells. Eighty- or jointly. Then Z tests were applied to compare the differ- seven patients with HBV DNA positive benign liver dis- ence of AUROC. Two-tailed P value less than 0.05 was de- ease (including 47 cases of HBV-related hepatocirrhosis fined statistically significant. and 40 cases of Hepatitis B) and 80 healthy individuals were selected during the same period as control. Benign Results liver diseases were ascertained by image tests or ultra- Patient demographics and tumor characteristics sonography detection. There was no evidence of any The cut-off value of AFP and PIVKA-II commonly used cancer or inflammatory disease from blood test results was 20 ng/ml and 40mAU/ml respectively. Based on this Si et al. Infectious Agents and Cancer (2020) 15:70 Page 3 of 7 critical value, patient demographics and tumor charac- 0.935) for PIVKA-II. The combination of AFP and teristics were outlined in Table 1. As shown in Table 1, PIVKA-II improved the diagnostic performance for we found that AFP and PIVKA-II had strong correlation HBV-related HCC (AUC 0.917; 95% CI, 0.886 ~ 0.948). with tumor size (measured by diameter) and differenti- The diagnostic values of AFP and PIVKA-II combined ation as well as vascular invasion. detection or single assay of PIVKA-II were better than that of separate assay of AFP (Z was 5.927 and 4.51 re- AFP and PIVKA-II serum levels in experimental and spectively, P all < 0.001). There was no significant differ- control group ence of diagnostic accuracy between joint test of the two The median levels of AFP and PIVKA-II in HBV-related biomarkers and PIVKA-II detected singly (Z was 1.795, HCC patients were 24.64 (IQR 4.38 ~ 528.82) and 334.08 P = 0.0727). The optimal cut-off value of HBV-related (IQR 60.88 ~ 5095.10), while their concentrations of con- HCC diagnosis was 21.8 ng/ml for AFP and 41.74mAU/ trol group were 3.20 (IQR 1.90 ~ 9.60) and 22.17 (IQR ml for PIVKA-II. At the optimal cut-off value of AFP 17.59 ~ 30.05) respectively. As shown in the Fig. 1, the and PIVKA-II, sensitivity and specificity in diagnosis of AFP and PIVKA-II levels were significantly higher in the HCC were reflected in Fig. 2. HBV-related HCC group than that in the control group (Z was 7.428, 11.243 respectively, P all < 0.01). There Correlations between AFP, PIVKA-II serum levels and was no significant difference of serum AFP and PIVKA- tumor differentiation and size (measured by diameter) of II level between patients with benign liver disease and HBV-related HCC healthy people in the control group. Above results vali- The AFP, PIVKA-II concentration showed significant dated that AFP and PIVKA-II played a significant role in differences in well/moderate/poor differentiation as well the diagnosis of HBV-related HCC. as tumor size of HBV-related HCC. Generally, the serum levels of AFP and PIVKA-II were positively correlated Comparison of AFP and PIVKA-II single and combined with tumor differentiation and size, just as shown in detection in HBV-related HCC diagnosis Fig. 3. The ROC curve was plotted to compare diagnostic values of AFP and PIVKA-II detected singly or jointly in Predictive value of AFP and PIVKA-II for HBV-related HCC HBV-related HCC and identify their cut-off values that vascular invasion would best distinguish patients with HBV-related HCC The positive results of H&E and immunohistochemical from control group. As pictured in the Fig. 2, the AUC staining in HBV-related HCC tissues with vascular inva- of HBV-related HCC diagnosis was 0.765 (95% CI, sion were shown in Fig. 4 (A and B). The median levels 0.713 ~ 0.8170) for AFP, and 0.901 (95% CI, 0.868 ~ of AFP and PIVKA-II in HBV-related HCC patients Table 1 Correlations between AFP and PIVKA-II expression and clinicopathologic variables of HBV-related HCC patients Si et al. Infectious Agents and Cancer (2020) 15:70 Page 4 of 7 Fig. 1 Log transformation was used on the AFP and PIVKA-II values to account for the large range of values for both markers. Log values of serum levels of AFP (a) and PIVKA-II (b) in HBV-related HCC and control group were compared by box plots. AFP: alpha fetoprotein, PIVKA-II: prothrombin induced by vitamin K absence- II. *P < 0.01 without vascular invasion were 15 (IQR 3.4 ~ 69) and invasion was obviously different. High AFP and PIVKA- 174.71 (IQR 46.76 ~ 1156.6), while their concentrations II expression was significantly associated with the of patients with vascular invasion were 45 (IQR 6.37 ~ presence of vascular invasion (Z was 2.683, 2.463 re- 1039.2) and 549.3 (IQR 65.13 ~ 7805.3) respectively. As spectively, P = 0.007 and 0.014). The AFP level > 64.4 ng/ shown in the Fig. 4 (C and D), the AFP and PIVKA-II ml or PIVKA-II level > 957.61mAU/ml was the predictor level in HBV-related HCC with or without vascular of vascular invasion. Fig. 2 ROCs curve comparing value of AFP, PIVKA-II and the combination of them as diagnostic markers for HBV-related HCC. Sensibility and specificity of the two kind of markers in detecting HBV-related HCC was also listed. AFP: alpha fetoprotein, PIVKA-II: protein induced by vitamin K absence-II Si et al. Infectious Agents and Cancer (2020) 15:70 Page 5 of 7 Fig. 3 Log values of serum levels of AFP (a and c) and PIVKA-II (b and d) were used to compare difference between their serum levels and tumor differentiation and size (measured by diameter) of HBV-related HCC. Among them, grade I and grade II were considered as well and moderate differentiation respectively while grade III or IV were regarded as poor differentiation. Based on the HBV-related HCC diameter, the experimental group were divided into the ≤5 cm, > 5 but ≤10 cm and > 10 cm group. AFP: alpha fetoprotein, PIVKA-II: protein induced by vitamin K absence-II. *P < 0.05 but P > 0.05 Discussion group, the level of AFP and PIVKA-II in experimental The incidence of hepatocellular carcinoma is increasing an- group was significantly higher. Our results validated that nually, thus early diagnoses and treatments are particularly AFP and PIVKA-II played a significant role in the diag- important. AFP is a glycoprotein that is the most common nosis of HBV-related HCC. The optimal cut-off values biomarker for diagnosing HCC. But it has not yet become of HBV-related HCC diagnosis in our study were 21.8 an optimal biomarker for diagnostic purposes because it ng/ml for AFP and 41.74mAU/ml for PIVKA-II respect- lacks high sensitivity and specificity [15]. PIVKA-II also ively, which were in close agreement with their cutoff known as des-gamma-carboxyprothrombin (DCP) is an im- values used currently. The combination of AFP and mature form of prothrombin without any coagulative func- PIVKA-II slightly improved the diagnostic performance, tion [16]. PIVKA-II is a specific marker for HCC, which is and the serum PIVKA-II level had a better diagnostic poorly related to AFP and exhibits higher sensitivity and value than AFP. These findings were in accordance with specificity than AFP in diagnosing HCC [17, 18]. conclusions from other studies [19–23]. The serum In this study, we evaluated the performance of AFP levels of AFP and PIVKA-II were positively correlated and PIVKA-II for the diagnosis of HBV-related HCC with tumor differentiation and size. High AFP and and explored the relationship between them and differ- PIVKA-II expression was significantly associated with ent clinicopathologic features, such as vascular invasion, the presence of vascular invasion. The AFP level > 64.4 tumor differentiation and size. Compared with control ng/ml or PIVKA-II level > 957.61mAU/ml was the best Si et al. Infectious Agents and Cancer (2020) 15:70 Page 6 of 7 Fig. 4 The arrow in (a) showed patent microscopic invasion of a vessel by neoplastic cells (H&E staining; magnification X100). With anti-CD34 immunohistochemistry (b), vascular invasion was confirmed by the presence of small nests of malignant cells inside the vessels (magnification X200). Log values of serum levels of AFP (c) and PIVKA-II (d) in HBV-related HCC with and without vascular invasion were compared by box plots. AFP: alpha fetoprotein, PIVKA-II: protein induced by vitamin K absence-II. *P < 0.05 and **P < 0.01 critical value to predict the presence and absence of vas- good repeatability and high test efficiency. At the same cular invasion. time, when studying the relationship between AFP, The conclusions about the relation between AFP, PIVKA-II level and tumor size, all the selected HCC PIVKA-II and clinicopathologic features (such as vascu- cases were all single tumors and multiple tumors were lar invasion, tumor differentiation and size) were differ- excluded by imaging examinations. Accordingly, the ent, even controversial [12–14, 24–27]. There were two conclusions were more persuasive. However, data of this main reasons for the different conclusions of previous study were obtained in a single hospital, and the number studies. One important factor was research cancer object of participants was small. Further research should spend which was not strictly screened. Hence they did not dis- more time and get more detailed information, for in- tinguish the amount and source of tumors. The other stance, we were not sure whether PIVKA-II correlates reason was related to detection instruments and with size or grade better than AFP. methods, the levels of AFP and PIVKA-II varied accord- ing to instruments and methods used. Based on the Conclusions above two reasons caused the contradiction between dif- In conclusion, PIVKA-II is the most useful single bio- ferent research. Tumor subjects in our study were HBV- marker to diagnose the presence of HBV-related HCC. related primary liver cancer, then immunofluorescence Combining the AFP and PIVKA-II further improves the assay and chemiluminescence immunoassay were used diagnostic performance. Moreover, their concentrations to measure AFP and PIVKA-II respectively. The play an important role in judging tumor size, tumor cell methods were accurate which had the advantages of differentiation and vascular invasion. Si et al. Infectious Agents and Cancer (2020) 15:70 Page 7 of 7 Acknowledgments liver transplantation for hepatocellular carcinoma. Am J Transplant. 2009; We appreciated the contributions of Department of Hepatobiliary Surgery, 9(10):2362–71. Shandong Provincial Hospital affiliated to Shandong University. 11. Shirabe K, Itoh S, Yoshizumi T, Soejima Y, Taketomi A, Aishima S, et al. The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of Authors’ contributions des-gamma-carboxy prothrombin. J Surg Oncol. 2007;95(3):235–40. ZL conceived the project and designed the experiments. CP, FC, ZL, BL 12. Saitta C, Raffa G, Alibrandi A, Brancatelli S, Lombardo D, Tripodi G, et al. performed the data extraction and analyzation; YS, XW, wrote and revised PIVKA-II is a useful tool for diagnostic characterization of ultrasound- the manuscript. GF, CW, YZ, XS clinically managed the patients. All authors detected liver nodules in cirrhotic patients. Medicine (Baltimore). 2017; read and approved the final version of the manuscript. 96(26):e7266. 13. Wang BL, Tan QW, Gao XH, Wu J, Guo W. Elevated PIVKA-II is associated Funding with early recurrence and poor prognosis in BCLC 0-a hepatocellular None. carcinomas. Asian Pac J Cancer Prev. 2014;15(16):6673–8. 14. Wu J, Xiang Z, Bai L, He L, Tan L, Hu M, et al. Diagnostic value of serum Availability of data and materials PIVKA-II levels for BCLC early hepatocellular carcinoma and correlation with The datasets used and/or analysed during the current study are available HBV DNA. Cancer Biomark. 2018;23(2):235–42. from the corresponding author on reasonable request. 15. Lim TS, Kim DY, Han KH, Kim HS, Shin SH, Jung KS, et al. Combined use of AFP, PIVKA-II, and AFP-L3 as tumor markers enhances diagnostic accuracy Ethics approval and consent to participate for hepatocellular carcinoma in cirrhotic patients. Scand J Gastroenterol. This study was approved by Ethics Committee of the Shandong Provincial 2016;51(3):344–53. Hospital affiliated to Shandong University. In this study, written informed 16. Svobodova S, Karlikova M, Topolcan O, Pecen L, Pestova M, Kott O, et al. consent was obtained from the patients or their families, and patient PIVKA-II as a potential new biomarker for hepatocellular carcinoma - a pilot anonymity was preserved. study. In Vivo. 2018;32(6):1551–4. 17. Abdel-Aziz MM, Elshal MF, Abass AT, El-Kafrawy S, Ezzat S, Abdel-Wahab M. Consent for publication Comparison of AFP-L3 and p53 antigen concentration with alpha- Not applicable. fetoprotein as serum markers for hepatocellular carcinoma. Clin Lab. 2016; 62(6):1121–9. Competing interests 18. Seo SI, Kim HS, Kim WJ, Shin WG, Kim DJ, Kim KH, et al. Diagnostic value of The authors declare that they have no competing interest. PIVKA-II and alpha-fetoprotein in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2015;21(13):3928–35. Author details 19. Durazo FA, Blatt LM, Corey WG, Lin JH, Han S, Saab S, et al. Des-gamma- Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic College of Medicine, Shandong University, Jinan 250021, Shandong, PR hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. China. Department of Clinical Laboratory, Shandong Provincial Hospital 2008;23(10):1541–8. Affiliated to Shandong First Medical University, Jinan 250021, Shandong, PR 20. Li C, Zhang Z, Zhang P, Liu J. Diagnostic accuracy of des-gamma-carboxy China. Department of Hepatobiliary Surgery, Shandong Provincial Hospital prothrombin versus alpha-fetoprotein for hepatocellular carcinoma: a Affiliated to Shandong First Medical University, Jinan 250021, Shandong, PR systematic review. Hepatol Res. 2014;44(10):E11–25. China. 21. Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, et al. Des- gamma carboxyprothrombin can differentiate hepatocellular carcinoma Received: 7 August 2020 Accepted: 13 November 2020 from nonmalignant chronic liver disease in american patients. Hepatology. 2003;37(5):1114–21. 22. Pote N, Cauchy F, Albuquerque M, Voitot H, Belghiti J, Castera L, et al. References Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. 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Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation

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Abstract

Background: To explore the value of alpha fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of HBV-related hepatocellular carcinoma (HCC) and their relationship with vascular invasion, tumor differentiation and size. Methods: A total of 433 participants were enrolled in this study including 266 cases with HBV-related HCC, 87 cases with HBV DNA positive benign liver disease and 80 healthy individuals. Then we explored the correlation between AFP, PIVKA-II serum level and several pathological features such as vascular invasion, tumor differentiation and size. The value of these two markers used singly or jointly in diagnosing HBV-related HCC was evaluated by receiver operating characteristic (ROC) curve. The ROC curve was also plotted to identify AFP, PIVKA-II serum cut-off values that would best distinguish HBV-related HCC patients with and without vascular invasion. Results: The level of AFP and PIVKA-II in HBV-related HCC group was significantly higher (Z was 7.428, 11.243 respectively, all P < 0.01). When AFP and PIVKA-II were used as the individual tumor marker, the areas under the ROC curve (AUC) of HBV-related HCC diagnosis were 0.765 (95% CI, 0.713 ~ 0.8170) for AFP, 0.901 (95% CI, 0.868 ~ 0.935) for PIVKA-II, and 0.917 (95% CI, 0.886 ~ 0.948) for AFP and PIVKA-II simultaneously. The serum levels of AFP and PIVKA-II were positively correlated with tumor differentiation and size. High AFP and PIVKA-II expression was significantly associated with the presence of vascular invasion (P was 0.007 and 0.014 respectively). The AFP level > 64.4 ng/ml or PIVKA-II level > 957.61mAU/ml was the best critical value to predict the presence of vascular invasion. Conclusion: Our results validate that AFP and PIVKA-II play a significant role in the diagnosis of HBV-related HCC. The diagnostic value of AFP and PIVKA-II combined detection or single assay of PIVKA-II is higher than that of separate assay of AFP. Moreover, their concentration has important clinical value in judging tumor size, tumor cell differentiation and vascular invasion. Keywords: HBV-related hepatocellular carcinoma, Alpha-fetoprotein, PIVKA-II, Vascular invasion * Correspondence: luzhiming@sdu.edu.cn Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, PR China Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, PR China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Si et al. Infectious Agents and Cancer (2020) 15:70 Page 2 of 7 Background with healthy individuals. Participants with Haemocoagu- HCC is currently the fifth most common malignant latory disorders, vitamin K uptake disorders and intake tumor and the third leading cause of cancer related of vitamin K blocking agents were excluded. Informed death worldwide [1]. There are close relationships consents were obtained from all participants. among chronic viral hepatitis (such as Hepatitis B and Hepatitis C), posthepatitic cirrhosis and HCC [2–4]. For Measurement of AFP and PIVKA-II the lack of typical symptoms of HCC in early stage, it is The contents of AFP and PIVKA-II were detected in the generally not easy to diagnose. More than 80% HCC pa- same serum samples respectively. AFP was measured tients are diagnosed at the middle or late stages. There- using the method of immunofluorescence on automatic fore, it is urgent to identify effective and specific electrophoresis fluorescence immunoassay analyzer biomarkers that provide early predictive potential for (mTAS Wako i30, Japan). The cut-off value was set at diagnosis of HCC [5]. 20 ng/ml. Serum levels of PIVKA-II were detected by AFP is a kind of glycoprotein that is often associated chemiluminescence enzyme immunoassay on automatic with HCC. However, AFP levels also increase in preg- chemiluminescence immunoassay instrument (LUMI- nancy and some benign diseases such as severe hepatitis PULSE® G1200, Japan). The cut-off value was 40mAU/ and cirrhosis. AFP is not significantly increased in about ml. The above reagents required were all original kit and 35% ~ 40% of the HCC patients, especially for small the standard operation procedure was followed strictly HCC [6, 7]. during the test. PIVKA-II is an abnormal form of prothrombin, which has been used as a good diagnostic biomarker for HCC Confirmation of vascular invasion [8–10]. There is now considerable evidence that PIVKA- Firstly, microscopic infiltration of the vessels at the per- II is an independent prognostic factor after liver surgery, iphery of the HBV-related HCC nodules was searched in such as hepatic resection or liver transplantation [11]. In all native livers by hematoxylin-eosin (H&E) staining. addition, PIVKA-II is influenced by many non-tumor Then, tumor vessel invasion was assessed by identifying factors, such as coagulation dysfunction, liver cirrhosis neoplastic emboli within the tumor vessels stained by and so on [8]. the mouse monoclonal antibody against CD34 protein. There were few studies on the correlation between the The stained slides were blindly and randomly examined above two indicators and vascular invasion, tumor differ- by the same pathologist who had already evaluated H&E entiation and size. And the conclusions are controversial sections. [12–14]. The aim of the study was to evaluate the diag- nostic value of PIVKA-II and AFP in the diagnosis of Statistical analysis HBV-related HCC and futher analysis the level of AFP IBM SPSS statistical software (version 22.0, USA) and and PIVKA-II in HBV-related HCC patients with differ- MedCalc (version 15.2.2.0, Belgium) were used for all statis- ent clinicopathologic characteristics such as tumor dif- tical analysis. It was found that the concentration levels of ferentiation and vascular invasion. AFP and PIVKA-II were skew distribution. Each variable was represented as median with interquartile range (IQR). Materials and methods Multi-numerical variables were compared by Kruskal- Patients Wallis test, and the nonparametric Mann-Whitney test was Two hundred sixty-six cases of HBV-related hepatocel- applied to compare the differences between two numerical lular carcinoma which were newly diagnosed in variables. Log transformation was used for AFP and Shangdong Provincial Hospital from January 2017 to PIVKA-II values to analyse the large range of values among December 2018 were recruited as experimental group. the different groups for the markers. The transformed data All cases were confirmed by pathological examination. were compared by box plots. Categorical variables were Pathological report of HBV-related HCC included tumor expressed in percentage and compared with the Pearson diameter and differentiation. Vascular invasion was de- Chi-square test. ROC Curves and AUROC were calculated fined by the presence of tumor cells forming a thrombus to evaluate the diagnostic value of AFP and PIVKA-II singly in a vascular space lined by endothelial cells. Eighty- or jointly. Then Z tests were applied to compare the differ- seven patients with HBV DNA positive benign liver dis- ence of AUROC. Two-tailed P value less than 0.05 was de- ease (including 47 cases of HBV-related hepatocirrhosis fined statistically significant. and 40 cases of Hepatitis B) and 80 healthy individuals were selected during the same period as control. Benign Results liver diseases were ascertained by image tests or ultra- Patient demographics and tumor characteristics sonography detection. There was no evidence of any The cut-off value of AFP and PIVKA-II commonly used cancer or inflammatory disease from blood test results was 20 ng/ml and 40mAU/ml respectively. Based on this Si et al. Infectious Agents and Cancer (2020) 15:70 Page 3 of 7 critical value, patient demographics and tumor charac- 0.935) for PIVKA-II. The combination of AFP and teristics were outlined in Table 1. As shown in Table 1, PIVKA-II improved the diagnostic performance for we found that AFP and PIVKA-II had strong correlation HBV-related HCC (AUC 0.917; 95% CI, 0.886 ~ 0.948). with tumor size (measured by diameter) and differenti- The diagnostic values of AFP and PIVKA-II combined ation as well as vascular invasion. detection or single assay of PIVKA-II were better than that of separate assay of AFP (Z was 5.927 and 4.51 re- AFP and PIVKA-II serum levels in experimental and spectively, P all < 0.001). There was no significant differ- control group ence of diagnostic accuracy between joint test of the two The median levels of AFP and PIVKA-II in HBV-related biomarkers and PIVKA-II detected singly (Z was 1.795, HCC patients were 24.64 (IQR 4.38 ~ 528.82) and 334.08 P = 0.0727). The optimal cut-off value of HBV-related (IQR 60.88 ~ 5095.10), while their concentrations of con- HCC diagnosis was 21.8 ng/ml for AFP and 41.74mAU/ trol group were 3.20 (IQR 1.90 ~ 9.60) and 22.17 (IQR ml for PIVKA-II. At the optimal cut-off value of AFP 17.59 ~ 30.05) respectively. As shown in the Fig. 1, the and PIVKA-II, sensitivity and specificity in diagnosis of AFP and PIVKA-II levels were significantly higher in the HCC were reflected in Fig. 2. HBV-related HCC group than that in the control group (Z was 7.428, 11.243 respectively, P all < 0.01). There Correlations between AFP, PIVKA-II serum levels and was no significant difference of serum AFP and PIVKA- tumor differentiation and size (measured by diameter) of II level between patients with benign liver disease and HBV-related HCC healthy people in the control group. Above results vali- The AFP, PIVKA-II concentration showed significant dated that AFP and PIVKA-II played a significant role in differences in well/moderate/poor differentiation as well the diagnosis of HBV-related HCC. as tumor size of HBV-related HCC. Generally, the serum levels of AFP and PIVKA-II were positively correlated Comparison of AFP and PIVKA-II single and combined with tumor differentiation and size, just as shown in detection in HBV-related HCC diagnosis Fig. 3. The ROC curve was plotted to compare diagnostic values of AFP and PIVKA-II detected singly or jointly in Predictive value of AFP and PIVKA-II for HBV-related HCC HBV-related HCC and identify their cut-off values that vascular invasion would best distinguish patients with HBV-related HCC The positive results of H&E and immunohistochemical from control group. As pictured in the Fig. 2, the AUC staining in HBV-related HCC tissues with vascular inva- of HBV-related HCC diagnosis was 0.765 (95% CI, sion were shown in Fig. 4 (A and B). The median levels 0.713 ~ 0.8170) for AFP, and 0.901 (95% CI, 0.868 ~ of AFP and PIVKA-II in HBV-related HCC patients Table 1 Correlations between AFP and PIVKA-II expression and clinicopathologic variables of HBV-related HCC patients Si et al. Infectious Agents and Cancer (2020) 15:70 Page 4 of 7 Fig. 1 Log transformation was used on the AFP and PIVKA-II values to account for the large range of values for both markers. Log values of serum levels of AFP (a) and PIVKA-II (b) in HBV-related HCC and control group were compared by box plots. AFP: alpha fetoprotein, PIVKA-II: prothrombin induced by vitamin K absence- II. *P < 0.01 without vascular invasion were 15 (IQR 3.4 ~ 69) and invasion was obviously different. High AFP and PIVKA- 174.71 (IQR 46.76 ~ 1156.6), while their concentrations II expression was significantly associated with the of patients with vascular invasion were 45 (IQR 6.37 ~ presence of vascular invasion (Z was 2.683, 2.463 re- 1039.2) and 549.3 (IQR 65.13 ~ 7805.3) respectively. As spectively, P = 0.007 and 0.014). The AFP level > 64.4 ng/ shown in the Fig. 4 (C and D), the AFP and PIVKA-II ml or PIVKA-II level > 957.61mAU/ml was the predictor level in HBV-related HCC with or without vascular of vascular invasion. Fig. 2 ROCs curve comparing value of AFP, PIVKA-II and the combination of them as diagnostic markers for HBV-related HCC. Sensibility and specificity of the two kind of markers in detecting HBV-related HCC was also listed. AFP: alpha fetoprotein, PIVKA-II: protein induced by vitamin K absence-II Si et al. Infectious Agents and Cancer (2020) 15:70 Page 5 of 7 Fig. 3 Log values of serum levels of AFP (a and c) and PIVKA-II (b and d) were used to compare difference between their serum levels and tumor differentiation and size (measured by diameter) of HBV-related HCC. Among them, grade I and grade II were considered as well and moderate differentiation respectively while grade III or IV were regarded as poor differentiation. Based on the HBV-related HCC diameter, the experimental group were divided into the ≤5 cm, > 5 but ≤10 cm and > 10 cm group. AFP: alpha fetoprotein, PIVKA-II: protein induced by vitamin K absence-II. *P < 0.05 but P > 0.05 Discussion group, the level of AFP and PIVKA-II in experimental The incidence of hepatocellular carcinoma is increasing an- group was significantly higher. Our results validated that nually, thus early diagnoses and treatments are particularly AFP and PIVKA-II played a significant role in the diag- important. AFP is a glycoprotein that is the most common nosis of HBV-related HCC. The optimal cut-off values biomarker for diagnosing HCC. But it has not yet become of HBV-related HCC diagnosis in our study were 21.8 an optimal biomarker for diagnostic purposes because it ng/ml for AFP and 41.74mAU/ml for PIVKA-II respect- lacks high sensitivity and specificity [15]. PIVKA-II also ively, which were in close agreement with their cutoff known as des-gamma-carboxyprothrombin (DCP) is an im- values used currently. The combination of AFP and mature form of prothrombin without any coagulative func- PIVKA-II slightly improved the diagnostic performance, tion [16]. PIVKA-II is a specific marker for HCC, which is and the serum PIVKA-II level had a better diagnostic poorly related to AFP and exhibits higher sensitivity and value than AFP. These findings were in accordance with specificity than AFP in diagnosing HCC [17, 18]. conclusions from other studies [19–23]. The serum In this study, we evaluated the performance of AFP levels of AFP and PIVKA-II were positively correlated and PIVKA-II for the diagnosis of HBV-related HCC with tumor differentiation and size. High AFP and and explored the relationship between them and differ- PIVKA-II expression was significantly associated with ent clinicopathologic features, such as vascular invasion, the presence of vascular invasion. The AFP level > 64.4 tumor differentiation and size. Compared with control ng/ml or PIVKA-II level > 957.61mAU/ml was the best Si et al. Infectious Agents and Cancer (2020) 15:70 Page 6 of 7 Fig. 4 The arrow in (a) showed patent microscopic invasion of a vessel by neoplastic cells (H&E staining; magnification X100). With anti-CD34 immunohistochemistry (b), vascular invasion was confirmed by the presence of small nests of malignant cells inside the vessels (magnification X200). Log values of serum levels of AFP (c) and PIVKA-II (d) in HBV-related HCC with and without vascular invasion were compared by box plots. AFP: alpha fetoprotein, PIVKA-II: protein induced by vitamin K absence-II. *P < 0.05 and **P < 0.01 critical value to predict the presence and absence of vas- good repeatability and high test efficiency. At the same cular invasion. time, when studying the relationship between AFP, The conclusions about the relation between AFP, PIVKA-II level and tumor size, all the selected HCC PIVKA-II and clinicopathologic features (such as vascu- cases were all single tumors and multiple tumors were lar invasion, tumor differentiation and size) were differ- excluded by imaging examinations. Accordingly, the ent, even controversial [12–14, 24–27]. There were two conclusions were more persuasive. However, data of this main reasons for the different conclusions of previous study were obtained in a single hospital, and the number studies. One important factor was research cancer object of participants was small. Further research should spend which was not strictly screened. Hence they did not dis- more time and get more detailed information, for in- tinguish the amount and source of tumors. The other stance, we were not sure whether PIVKA-II correlates reason was related to detection instruments and with size or grade better than AFP. methods, the levels of AFP and PIVKA-II varied accord- ing to instruments and methods used. Based on the Conclusions above two reasons caused the contradiction between dif- In conclusion, PIVKA-II is the most useful single bio- ferent research. Tumor subjects in our study were HBV- marker to diagnose the presence of HBV-related HCC. related primary liver cancer, then immunofluorescence Combining the AFP and PIVKA-II further improves the assay and chemiluminescence immunoassay were used diagnostic performance. Moreover, their concentrations to measure AFP and PIVKA-II respectively. The play an important role in judging tumor size, tumor cell methods were accurate which had the advantages of differentiation and vascular invasion. Si et al. Infectious Agents and Cancer (2020) 15:70 Page 7 of 7 Acknowledgments liver transplantation for hepatocellular carcinoma. Am J Transplant. 2009; We appreciated the contributions of Department of Hepatobiliary Surgery, 9(10):2362–71. Shandong Provincial Hospital affiliated to Shandong University. 11. Shirabe K, Itoh S, Yoshizumi T, Soejima Y, Taketomi A, Aishima S, et al. The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of Authors’ contributions des-gamma-carboxy prothrombin. J Surg Oncol. 2007;95(3):235–40. ZL conceived the project and designed the experiments. CP, FC, ZL, BL 12. Saitta C, Raffa G, Alibrandi A, Brancatelli S, Lombardo D, Tripodi G, et al. performed the data extraction and analyzation; YS, XW, wrote and revised PIVKA-II is a useful tool for diagnostic characterization of ultrasound- the manuscript. GF, CW, YZ, XS clinically managed the patients. All authors detected liver nodules in cirrhotic patients. Medicine (Baltimore). 2017; read and approved the final version of the manuscript. 96(26):e7266. 13. Wang BL, Tan QW, Gao XH, Wu J, Guo W. Elevated PIVKA-II is associated Funding with early recurrence and poor prognosis in BCLC 0-a hepatocellular None. carcinomas. Asian Pac J Cancer Prev. 2014;15(16):6673–8. 14. Wu J, Xiang Z, Bai L, He L, Tan L, Hu M, et al. Diagnostic value of serum Availability of data and materials PIVKA-II levels for BCLC early hepatocellular carcinoma and correlation with The datasets used and/or analysed during the current study are available HBV DNA. Cancer Biomark. 2018;23(2):235–42. from the corresponding author on reasonable request. 15. Lim TS, Kim DY, Han KH, Kim HS, Shin SH, Jung KS, et al. Combined use of AFP, PIVKA-II, and AFP-L3 as tumor markers enhances diagnostic accuracy Ethics approval and consent to participate for hepatocellular carcinoma in cirrhotic patients. Scand J Gastroenterol. This study was approved by Ethics Committee of the Shandong Provincial 2016;51(3):344–53. Hospital affiliated to Shandong University. In this study, written informed 16. Svobodova S, Karlikova M, Topolcan O, Pecen L, Pestova M, Kott O, et al. consent was obtained from the patients or their families, and patient PIVKA-II as a potential new biomarker for hepatocellular carcinoma - a pilot anonymity was preserved. study. In Vivo. 2018;32(6):1551–4. 17. Abdel-Aziz MM, Elshal MF, Abass AT, El-Kafrawy S, Ezzat S, Abdel-Wahab M. Consent for publication Comparison of AFP-L3 and p53 antigen concentration with alpha- Not applicable. fetoprotein as serum markers for hepatocellular carcinoma. Clin Lab. 2016; 62(6):1121–9. Competing interests 18. Seo SI, Kim HS, Kim WJ, Shin WG, Kim DJ, Kim KH, et al. Diagnostic value of The authors declare that they have no competing interest. PIVKA-II and alpha-fetoprotein in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2015;21(13):3928–35. Author details 19. Durazo FA, Blatt LM, Corey WG, Lin JH, Han S, Saab S, et al. Des-gamma- Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic College of Medicine, Shandong University, Jinan 250021, Shandong, PR hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. China. Department of Clinical Laboratory, Shandong Provincial Hospital 2008;23(10):1541–8. 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